Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([CH:16]=O)[CH:3]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:23][O:24][NH2:25].CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])=[C:4]([CH:16]=[N:25][O:24][CH2:23][C:22]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:20]([Cl:19])[CH:21]=2)[CH:3]=1
Reactant: O=Cc1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOCc1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(Nc1ccc(Cl)cc1C=NOCc1ccc(Cl)c(Cl)c1)C(F)(F)F
Yield: 65.4 %

Procedure:
A solution of N-(4-chloro-2-formylphenyl)trifluoromethanesulfonamide 24 (163 mg, 0.57 mmol), O-(3,4-dichlorobenzyl)hydroxylamine hydrochloride (130 mg, 0.57 mmol) and anhydrous NaOAc (77 mg, 0.94 mmol) in EtOH (10 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CHCl3). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9) afforded N-{4-chloro-2-[(3,4-dichlorobenzyloxyimino)methyl]phenyl}trifluoromethanesulfonamide 97 (172 mg, 66%), as a colorless oil. 1H n.m.r. (200 MHz, CDCl3) δ10.65, br s, 1H, 8.14, s, 1H, 7.66, d, J=8.8 Hz, 1H, 7.51-7.45, m, 2H, 7.35, dd, J=2.4 and 8.8 Hz, 1H, 7.27-7.22, m, 2H, 5.12, s, 2H. HRMS (M+) 459.9422.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:21])[CH:12]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[N:11]=1.[I-].[Na+].Cl[CH2:36][C:37]1[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][N:38]=1>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH2:36][C:37]2[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][N:38]=2)[C:13](=[O:21])[CH:12]([N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[N:11]=1
Reactant: Cc1cccnc1CCl
Reactant: O=C1Nc2ccccc2C(c2ccccc2F)=NC1N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccnc1CN1C(=O)C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2F)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a suspension of sodium hydride (0.11 g of a 64% dispersion in mineral oil) in dry N,N-dimethylformamide (10 ml) was added (3RS)-2,3-dihydro-5-(2-fluorophenyl)-3-phthalimido-1H-1,4-benzodiazepin-2-one (1.00 g) under stirring for 2 hours at ambient temperature. To the mixture was added sodium iodide (0.42 g) and followed dropwise a solution of 2-chloromethyl-3-methyl-pyridine (0.389 g) in dry N,N-dimethylformamide (3 ml) at ambient temperature. The mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo, and the residue was taken up with ethyl acetate. The organic layer was washed with saturated sodium carbonate aqueous solution, dried over sodium sulfate, filtered and concentrated in vacuo to give (3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(3-methylpyridin-2-yl)methyl-3-phtalimido-1H-1,4-benzodiazepin-2-one (1.24 g). The product was used in a following reaction step without further purification.
Reaction SMILES: C([Mg]Br)C.[C:5]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[OH:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH2:23]=[O:24].C(N(CC)CC)C>C1COCC1.C1(C)C=CC=CC=1>[C:5]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([CH:23]=[O:24])[C:15]=1[OH:22])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:7])[CH3:6]
Reactant: COc1ccc(O)c(C(C)(C)c2ccccc2)c1
Reactant: C=O
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(C=O)c(O)c(C(C)(C)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
Into a 1 liter reactor thoroughly purged with nitrogen, 43.5 ml of an ether solution containing 130.7 mmol of ethylmagnesium bromide and 70 ml of THF were introduced. To the reactor, a solution containing 30.16 g (124.5 mmol) of 2-cumyl-4-methoxyphenol diluted with 80 ml of a THF was dropwise added at 0° C. over a period of 30 minutes. Then, 500 ml of toluene was added, and the system was heated to 100° C. to distill off about 40 ml of a mixed solution of ether and THF, whereby an opaque white slurry was obtained. After the slurry was cooled to 15° C., 9.04 g (301.3 mmol) of paraformaldehyde and 24.8 ml (178.0 mmol) of triethylamine were added, followed by stirring at 90° C. for 15 minutes. The reaction solution was allowed to cool to room temperature and then quenched with 84 ml of 18% hydrochloric acid. The organic layer was washed with 400 ml of water, 200 ml of a sodium hydrogencarbonate aqueous solution and a sodium chloride aqueous solution (200 ml×2), and then concentrated. The resulting liquid was purified by silica gel column chromatography to obtain 27.27 g (yield: 81%) of 3-cumyl-5-methoxysalicylaldehyde.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]2[C@H:22]3[C@H:32]([CH2:33][CH2:34][C@:17]12[CH3:18])[C@:30]1([CH3:31])[CH:25]([O:26][C:27](=[O:35])[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)=[O:15].C1([Se](O[Se](C2C=CC=CC=2)=O)=O)C=CC=CC=1>ClC1C=CC=CC=1.C(OCC)(=O)C>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:4]=1[NH:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]2[C@H:22]3[C@H:32]([CH2:33][CH2:34][C@:17]12[CH3:18])[C@:30]1([CH3:31])[CH:25]([O:26][C:27](=[O:35])[CH:28]=[CH:29]1)[CH2:24][CH2:23]3)=[O:15]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4OC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: O=[Se](O[Se](=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CCC4OC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Nc1cc(C(F)(F)F)ccc1C(F)(F)F

Procedure:
To a solution of N-(2',5'-bistrifluoromethylphenyl)-4-oxa-androstan-3-one-17β-carboxamide. (35 mg, 0.066 mmol, prepared according to the procedures of Example 8) in chlorobenzene (5 mL) was added benzeneseleninic anhydride (30 mg, 0.085 mmol). After stirring the reaction mixture at reflux temperature for overnight, the reaction mixture was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified by prep. tlc (50% EtOAc/hexane). Mass spec. M+ 530(m+1, observed).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH3:20])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:27]([O-])([N+]([O-])=O)=[O:28]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:27]=[O:28])[C:5]([N:7]([CH2:19][CH3:20])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 76.8 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-ethyl-3-D-glucopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.6 g of 1-(2-chloroethyl)-1-nitroso-3-ethyl-3-D-glucopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:84][C:85]([N:87]1[CH2:92][CH2:91][NH:90][CH2:89][CH2:88]1)=[O:86])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>CN(C=O)C>[CH2:77]([O:84][C:85]([N:87]1[CH2:92][CH2:91][N:90]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:5])=[O:43])[CH2:89][CH2:88]1)=[O:86])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 24 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 55 μl DIPEA, 64 mg HATU and 56 mg piperazine-1-carboxylic acid benzyl ester. After stirring for 24 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 360 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:31])[CH:13]=[CH:14][CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23]COC)=[C:19]([O:27]COC)[CH:18]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([NH:11][C:12](=[O:31])[CH:13]=[CH:14][CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:27])[CH:18]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: COCOc1ccc(C=CC=CC(=O)NC/C=C(\C)CCC=C(C)C)cc1OCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)=CCC/C(C)=C/CNC(=O)C=CC=Cc1ccc(O)c(O)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a solution of 1.96 g of 5-(3',4'-dimethoxymethoxyphenyl)pentadienoic acid geranylamide in 40 ml of methanol is added 0.09 g of p-toluenesulfonic acid monohydrate. The mixture is stirred at 50° C. for 3 hours. The reaction mixture is poured onto water and extracted with chloroform. The organic layer is washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to column chromatography on silica gel. From the fraction eluted with chloroform-methanol (99:1) is obtained 1.40 g of 5-(3',4'-dihydroxyphenyl)pentadienoic acid geranylamide (15). Spectroscopic data of the product support the structure of the formula (15) below.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>O>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[CH:7]=[C:2]([I:1])[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]2=[O:8])=[CH:19][CH:18]=1
Reactant: Cc1c(I)c[nH]c(=O)c1[N+](=O)[O-]
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(Cn2cc(I)c(C)c([N+](=O)[O-])c2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75 %

Procedure:
A mixture of 5-iodo-4-methyl-3-nitro-2-pyridone (2.90 g, 10.4 mmol) and sodium hydride (60% in oil, 0.44 g, 11 mmol) was stirred at rt for 2.5 hours. 4-Methoxybenzyl chloride (1.50 mL) was added, and the mixture was stirred at rt for 18 h. Water was added, and the mixture and extracted with ethyl acetate. The organic phase was washed, dried and evaporated. Chromatography of the residue over silica gel (35% ethyl acetate/petroleum ether) followed by crystallization from water gave 1-(4-methoxybenzyl)-5-iodo-4-methyl-3-nitro-2-pyridone (3.11 g, 75%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[H-].[Na+]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: BrCc1ccncc1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Ic1ccc(N(Cc2ccncc2)c2ncccn2)cc1
Yield: 23.7 %

Procedure:
In the same manner as in Reference Example 22, N-(4-iodophenyl)pyrimidin-2-amine (300 mg) and 4-bromomethylpyridine hydrobromide (307 mg) were reacted in the presence of sodium hydride to obtain N-(4-iodophenyl)-N-((pyridin-4-yl)methyl)pyrimidin-2-amine (93 mg).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:39])[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([CH:37]=O)=[CH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[N:32]=3)[N:27]=[CH:26][C:25]=2[Cl:36])[CH2:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.C(OCC)(=O)C>[C:9]([O:13][C:14](=[O:39])[NH:15][C@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]([CH2:37][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[N:32]=3)[N:27]=[CH:26][C:25]=2[Cl:36])[CH2:20][CH2:21]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: NCc1ccccc1
Reactant: COc1ccc2ncc(Cl)c(C=C(C=O)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2ncc(Cl)c(C=C(CNCc3ccccc3)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzylamine (360 mg, 3.36 mmol, 3.0 eq) is added at room temperature to a stirred solution of {trans-4-[2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-1-formyl-vinyl]-cyclohexyl}-carbamic acid tert-butyl ester (500 mg, 1.12 mmol, 1.0 eq) in ethanol (20 mL), followed by acetic acid (337 mg, 5.61 mmol, 5.0 eq) and sodium cyanoborohydride (352 mg, 5.61 mmol, 5.0 eq). After 2 hours stirring at room temperature, the reaction mixture is extracted with ethyl acetate (3×20 mL) and a saturated sodium hydrogen carbonate aqueous solution (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: ethyl acetate:petroleum ether, 3:1 to 1:1, v/v) to afford {trans-4-[1-(benzylamino-methyl)-2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-vinyl]-cyclohexyl}-carbamic acid tert-butyl ester as a light yellow solid (320 mg, 53% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10]1COC[CH2:11]1.C(OC(OCC)CBr)C>O>[Br:9][C:5]1[N:6]=[C:7]([Br:8])[C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[CH:4]=1
Reactant: C1CCOC1
Reactant: Nc1ncc(Br)nc1Br
Agent: CCOC(CBr)OCC
Solvent: O
Product: Brc1cn2ccnc2c(Br)n1

Procedure:
To a stirred suspension of 2-amino-3,5-dibrompyrazine (427 g, 1688 mmol) in water (6.4 L)/THF (482 mL), at rt was added bromacetaldehyde-diethylacetal (998 g, 5065 mmol) in one portion. After stirring under reflux for 4 h, the clear orange solution was stirred for an additional 15 h at rt. The suspension was filtered, and the remaining solid was washed with MeOH (2 L) and dried in vaccuo at 60° C. to yield 6,8-dibromo-imidazo[1,2-a]pyrazine as an off-white solid (500 g, 107% with residual MeOH): 1H-NMR (300 MHz, d6-DMSO): δ=9.02 (s, 1H), 8.23 (d, 1H), 7.89 (d, 1H) ppm. UPLC-MS: RT=0.80 min; m/z 277.9 [MH+]; required MW=276.9.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Cl:12])[CH:6]=1)=[O:4].[CH3:13][C:14]([O:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][C:29](B(O)O)=[CH:30][C:23]=2[CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15]>>[Cl:12][C:7]1[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[CH:9][C:8]=1[O:11][C:28]1[CH:29]=[CH:30][C:23]2[CH2:22][CH2:21][N:20]([C:18]([O:17][C:14]([CH3:13])([CH3:15])[CH3:16])=[O:19])[CH2:26][CH2:25][C:24]=2[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B(O)O)cc2CC1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(Cl)c1

Procedure:
The title compound was prepared from methyl 3-chloro-4-hydroxy benzoate (320 mg, 1.72 mmol) and (3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronic acid (E264, Step 2) using the method outlined in Example 264 Step 3 (211 mg, 29%); NMR (CDCl3) δ 1.49 (9H, s), 2.88 (4H, m), 3.56 (4H, m), 3.91 (3H, s), 6.78-6.89 (3H, m), 7.12 (H, m), 7.84 (H, m), 8.14 (H, s)
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[N:10]=[C:9]([C:20]3[N:21]=[N:22][N:23]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.CO.C1COCC1.[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=[O:14])[N:10]=[C:9]([C:20]3[N:21]=[N:22][N:23]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH:24]=3)[CH:8]=2)=[CH:34][CH:35]=1
Reactant: COc1ccc(Cn2cc(-c3cc(Cc4ccc(F)cc4)n(CC(=O)OC(C)(C)C)n3)nn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2cc(-c3cc(Cc4ccc(F)cc4)n(CC(=O)O)n3)nn2)cc1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a solution of tert-butyl {5-(4-fluorobenzyl)-3-[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]-1H-pyrazol-1-yl}acetate (14.0 g, 29.3 mmol) in mixed solvent of MeOH/THF (60 mL/20 mL) was added a solution of NaOH (3.5 g, 88 mmol) in H2O (20 mL) and the reaction mixture was stirred at room temperature for an hour. The mixture was evaporated and the residue was diluted with water (100 mL) and washed with EtOAc (2×100 mL). The aqueous layer was adjusted to pH=3-4 with conc. HCl. The precipitate was filtered and dried in vacuo to afford the title compound (11.0 g, 90.0%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]=3[C:4]3[C:12]2=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=3)=[CH:26][CH:25]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(=O)CCC3
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: Cc1ccc2c(c1)c1c(n2Cc2ccc(F)cc2)CCCC1=O
Reaction time: 0.33 h
Yield: 66.3 %

Procedure:
6-Methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.5457 g, 0.027 mol) is added to a slurry of pentane-washed NaH (0.1369 g, 0.0034 mol) in DMF (3 mL) and after stirring for 20 min, p-fluorobenzyl bromide (0.42 mL, 0.0034 mol) is added, followed by additional DMF (2 mL). After the slurry had stirred for 2.5 h, it is partitioned between water and ethyl acetate. The combined organic layers are washed with water, dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (200 mL) using dichloromethane (100%) to give 0.6929 g (82%) of the title compound. An aliquot is recrystallized from ethyl acetate/heptane; mp 209.5-210° C.; MS (ESI+) for C20H18FNO m/z 308.2 (M+H)+; IR (drift) 2939, 1629, 1510, 1467, 1449, 1413, 1362, 1225, 1219, 1190, 1158, 1107, 1094, 832, 797 cm−1; 1H NMR (CDCl3) δ2.23, 2.47, 2.59, 2.85, 5.27, 6.99, 7.05, 7.12, 8.11. Anal. Calcd for C20H18FNO: C, 78.15; H, 5.90; N, 4.56. Found: C, 77.64; H, 5.87; N, 4.44.
Reaction SMILES: Cl[C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:12][S-:13].[Na+].O>CN(C=O)C>[CH3:12][S:13][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5]
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cccc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
[step 1] Commercially available 3-chloro-2-nitroaniline (3.0 g, 17 mmol) was dissolved in DMF (87 mL), sodium thiomethoxide (1.54 g, 21 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was discontinued with water, and the mixture was extracted with ethyl acetate, and the extract was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was crystallized from isopropyl ether to give 3-(methylthio)-2-nitroaniline (2.5 g, 78%).
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:23]3[C:24]4([O:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][O:25]4)[C:22]=3[C:21]3[CH:32]=[CH:33][C:34]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:35][C:20]=3[CH2:19][CH2:18][C:17]=2[CH:41]=1)(=O)C>CO>[CH2:37]([O:36][C:34]1[CH:33]=[CH:32][C:21]2[C:22]3[C:24]4([O:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][O:25]4)[C:23]=3[C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][OH:6])=[CH:41][C:17]=3[CH2:18][CH2:19][C:20]=2[CH:35]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCOC(C)=O)ccc1C1=C2C12OCC(C)(C)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCO)ccc1C1=C2C12OCC(C)(C)CO2
Yield: 80.2 %

Procedure:
A solution of NaOH (1.2 mL, 1.2 mmol, 1 M aqueous solution) was added to solution of acetate 10 (0.593 g, 1.11 mmol) in MeOH:THF (10:3 mL) at room temperature, and the reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was partially concentrated under reduced pressure, diluted with EtOAc (approximately 25 mL) and water (approximately 10 mL), the organic layer was separated, washed with brine, and dried over anhydrous MgSO4. Solvents were evaporated under reduced pressure, and the residue was separated by chromatography (Hex:ExOAc:CH2Cl2 3:2:1+1.5% of Et3N) to provide 0.493 g (0.89 mmol, 81%) of an alcohol 11 as slightly yellow oil that crystallizes on standing. 1H NMR: 7.65 (dd, J=8.4, 2.4 Hz, 2H), 6.92-6.82 (m, 4H), 4.18 (t, J=4.4 Hz, 2H), 4.04 (t, J=6.4 Hz, 2H), 3.92 (m, 4H), 3.88 (t, J=4.4 Hz, 2H), 3.77 (t, J=4.4 Hz, 2H), 3.68 (t, J=4.4 Hz, 2H), 3.24 (d, J=10.8 Hz, 2H), 2.41 (d, J=10.8 Hz, 2H), 1.76 (p, J=7.2 Hz, 2H), 1.50 (six, J=7.6 Hz, 2H), 1.21 (s, 3H), 1.19 (s, 3H), 0.99 (t, J=7.2 Hz, 3H); 13C NMR: 159.8, 159.2, 147.4, 131.84, 131.75, 131.67, 131.57, 124.4, 123.6, 119.8, 119.1, 116.3, 116.2, 112.2, 84.1, 79.4, 72.8, 69.8, 68.0, 76.7, 62.0, 37.1, 31.5, 30.8, 22.9, 19.4, 14.2.
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1.[CH2:32](N(CC)CC)C.CI>C(Cl)Cl>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:26][CH2:27][N:28]([CH3:32])[CH2:29][CH2:30]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1
Reactant: FC1(F)Oc2ccc(-c3c[nH]c4ncc(-c5cnn(C6CCNCC6)c5)cc34)cc2O1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CI
Product: CN1CCC(n2cc(-c3cnc4[nH]cc(-c5ccc6c(c5)OC(F)(F)O6)c4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 324 (50 mg, 0.1182 mmol) in DCM was added triethylamine (17.9 mg, 0.236 mmol). Methyl iodide (18.3 mg, 0.130 mmol) was added to the reaction and stirred for 2 h at rt. The reaction mixture was diluted with dichloromethane and washed with water twice. The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified by flash column using 100-200 mesh silica gel. The compound was eluted at 2% methanol in chloroform as off white coloured solid 3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 341.